Onychomycosis is an infection of the nails which represents the most common nail disease worldwide. At the beginning of the past century this fungal infection was still considered as very rare, but its prevalence increased dramatically during the last decades of the century, reaching very high rates in the US (up to 14% of the general population) and in the EU (near 30% of selected populations) (Baran R, Hay R, Haneke E, Tosti A (Eds), Epidemiology. In: Onychomycosis—the current approach to diagnosis and therapy. London, Martin Dunitz, 1999: pp. 6-9). Presently, onychomycosis represents approximately 50% of all nail disorders. It is a fungal disease of the nail mostly caused by dermatophytes, such as Trichophyton rubrum, Trichophyton mentagrophytes and Epidermophyton floccosum, and is far more common on the toenails than on the fingernails.
Both genders appear to be equally affected. Onychomycosis may occur at any age but it is rare prior to puberty, and an increased incidence has been reported in the elderly population. Risk factors for onychomycosis are diabetes, nail psoriasis, hyperhidrosis, impaired peripheral circulation, nail trauma, tinea pedis and immunodeficiency (Tosti A, Hay R, Arenas-Guzmán R, Patients at risk of onychomycosis—risk factor identification and active prevention. J Eur Acad Dermatol Veneorol, 2005, 19:13-16).
The pharmacological treatment of this difficult to eradicate and often recurring disease is done by oral terbinafine, which is actually considered as the golden standard for onychomycosis worldwide, and is reported to achieve a complete cure in 38% of patients. Terbinafine is an antifungal agent provided with a strong activity on dermatophytes and molds. Commercial products containing terbinafine are worldwide available as 250 mg tablets, for treatment of onychomycosis. Standard dosage is one tablet a day orally administered for 12 weeks.
Itraconazole and fluconazole are reportedly less effective. None of those drugs, terbinafine, itraconazole or fluconazole, is devoid of rare but serious, sometimes fatal adverse events (Ajit C, Suvannasankha A, Zaeri N, Munoz S J, Terbinafine-associated hepatotoxicity. Am J Med Sci. 2003; 325:292-5; Slørdal L, Spigset 0. Heart failure induced by non-cardiac drugs. Drug Saf. 2006; 29:567-86).
It is unacceptable that a patient risks life-threatening adverse reactions from a treatment of nail infections. For this reason topical treatments, including ciclopirox, amorolphine and tioconazole, are also available, although their effectiveness is even lower. Among topical treatments, the most effective is ciclopirox in a specifically designed nail formulation, which achieves about 13% of complete cure and almost 30% of responders after a 48 weeks of daily treatment followed by a 12-week follow up without treatment (Baran R, Tosti A, Hartmane I et al. An innovative water soluble biopolymer improves efficacy of ciclopirox nail lacquer in the management of onychomycosis. J Eur Acad Dermatol Veneorol, 2009, 23:773-781).
A large medical need is still present in the management of onychomycosis, in order to find treatments able to improve the rate of effectiveness and at the same time to decrease the risk of toxicity. One of the most evident things is that with oral treatments the patient is systemically exposed to an enormous quantity of the drug (21,000 mg per patient in the case of terbinafine) while less than 1/1,000 is the quantity of the drug which actually reaches the site of action, i.e. the nails. If there is the possibility to allow a direct application to the site of action, the systemic exposure, and consequently the intrinsic toxicity of the treatment, would be dramatically reduced, while the effectiveness should be maintained.
Attempts to formulate terbinafine in a topical composition to be applied directly on the affected areas are known in the art.
EP0515312 discloses compositions suitable to application on the nails containing terbinafine formulated in water insoluble polymeric film forming agents from the group of polyvinyl acetate or acrylic- and methacrylic-acid alkyl ester copolymerisates with quaternary ammonium groups or methylvinylether-maleic acid monoalkyl ester copolymerisates. No information on the real efficacy of those compositions was made available, though the fact that no commercial product having been developed from that teaching over 20 years later, may reasonably lead to conclude that no efficacy is to be expected from the matter disclosed herein. US2012/0128612A1 discloses compositions effective for application to nails comprising at least one volatile solvent, at least one film forming substance and at least one pyrimidone derivative with antifungal activity, where terbinafine may be optionally added to the composition as additional active ingredient. U.S. Pat. No. 5,681,849 discloses how to improve the dissolution of the active ingredient terbinafine and to improve spreadability by using a water soluble or water miscible nonionic surfactant. The disadvantage of such a composition is that it appears more suitable to application on skin than on nails, as it would be difficult to maintain the composition for a long time on the nail surface. U.S. Pat. No. 7,462,362B2 discloses an antifungal nail coat suitable to improve terbinafine penetration through the nail plate. Unfortunately, a nail lacquer containing 10% of terbinafine in the nail coat according to that invention was devoid of any efficacy in comparison to a placebo when applied daily for 48 weeks onto the nail surface of patients with onychomycosis, with rate of cure not overcoming 2.2% of patients daily treated by 48 weeks (Elewski B, Ghannoum M A, Mayser P et al. Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs. J Eur Acad Dermatol Veneorol, 2011, DOI: 10.1111/j.1468-3083.2011.04373.x). US2008/0261986A1 discloses a formulation suitable for iontophoresis comprising terbinafine, solvents and a penetration enhancer from the group of benzoic acid, oleic acid, salycilic acid, cysteine, acetylcisteine and urea. WO02/11764A2 discloses how to improve nail penetration of terbinafine by making several holes in the nail plate by means of a laser, in order to improve the terbinafine permeation from a composition to be put onto the nail surface. None of the aforementioned prior art was able to demonstrate effectiveness from the proposed compositions and technologies, moreover the last two appear as unfeasible in clinical setting from the practical point of view. WO02/07683A1 discloses antimycotic nail varnish compositions containing an antimycotic agent, a water soluble polymeric film-forming agent selected from hydroxalkyl and carboxyalkyl chitosans, ethyl acetate (as penetration enhancer), cetostearyl alcohol (as plasticizer), ethanol and water.
It has now been surprisingly found that a simpler composition of terbinafine, containing terbinafine as the sole active antimycotic ingredient, together with a low concentration of film forming agent and a proper solvent system, is effective in the treatment of onychomycosis even when it is administered once a week. Furthermore, the composition appears even more effective when it is applied once a day for the first month, then is applied once weekly until the end of treatment.